Growth factor delivery system for the healing of wounds and the prevention of inflammation and disease

ABSTRACT

The present invention features hydrogel drug delivery systems and methods of producing and using such systems for the treatment of wounds. The systems are based on a hydrogel into which a low concentration of growth factor, e.g., epidermal growth factor, is passively transferred from a dilute aqueous solution. When placed in contact with a wounded tissue, the growth factor passively transfers out of the contact lens to provide accelerated healing. The systems are applicable to ocular and other wound treatments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/971,820, filed Oct. 22, 2004, which is a divisional of U.S.application Ser. No. 10/340,434, filed Jan. 10, 2003, which is acontinuation-in-part of U.S. application Ser. No. 10/132,843, filed Apr.25, 2002, each of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

In general, the invention relates to the fields of hydrogels, drugdelivery systems, wound healing, and reduction of pain and inflammation.

Corneal wounds caused by injury, disease, or surgery represent a seriousmedical condition that may lead to loss of sight. For example,persistent epithelial defects can lead to stromal melting, which causesserious visual dysfunction. Wound healing of corneal mucosal tissue hastaken on increased importance with the advent of laser correctivesurgery to re-establish normal vision for people who do not wish to wearcontact lenses or spectacles. These laser surgical methods are used tocorrect vision for nearsightedness (myopia), farsightedness (hyperopia),and astigmatism. The methods include laser in situ keratomileusis(LASIK), laser epithelial keratomileusis (LASEK), and photo-refractivekeratectomy (PRK).

LASIK refers to the use of a laser to reshape the cornea withoutinvading the adjacent cell layers. During the LASIK procedure, amicrokeratome is used to separate the surface layers of the cornea andcreate a corneal flap (160-180 microns deep). This flap stays attachedto the rest of the cornea and is folded back on one side to expose thestroma of the cornea. The laser delivers pulses of ultraviolet lightonto the inner cornea (stroma). Each pulse removes a microscopic layerof the inner cornea to reshape the surface of the cornea. Fornearsighted patients, the procedure flattens the cornea. For farsightedpatients, the procedure increases the curvature of the cornea. Forastigmatism, selected tissues are removed at certain angles to make thecornea more spherical in shape. After exposure to the laser iscompleted, the corneal flap is replaced where it bonds without the needfor stitches. The anterior layers of the cornea (epithelium, Bowman'sLayer) are largely preserved. Once the surgery is completed, the eye isleft to heal normally with the exception of eye drops, which are used toprevent infection & swelling, with varying degrees of success. Followingthe surgery, patients are able to see clearly without depending onglasses or contacts.

During PRK, the surgeon removes the epithelium (the anterior layer ofthe cornea or Bowman's Layer), which is a thin layer of protective skinthat covers the cornea. This layer can be removed with an excimer laseror a brush. During the procedure, the patient stares at a fixationlight. In less than a minute, the laser removes the proper amount oftissue while it reshapes the surface of the cornea. The excimer laserdelivers pulses of ultraviolet light into the cornea. This exposure tolaser radiation reduces or eliminates nearsightedness by flattening thecentral cornea and relocating the focal point of the lens onto theretina rather than in front of it, which produces sharper vision.Following surgery, a bandage contact lens is placed on the eye for 2-3days. Because the epithelium was removed, patients may experience blurryvision for three to five days. Eye drops and the contact lens areeffective in reducing postoperative discomfort. The purpose of thecontact lens given to PRK patients post-surgically is to protect theleading edge of the corneal epithelium that is regenerating along thesurface of the eye, post-surgery. As patients blink, the newer leadingedge of the epithelium may be removed. As a result, recovery takeslonger and there is an increased risk of infection.

LASEK is similar to PRK but the epithelium is detached by using analcohol solution that weakens the epithelium and allows it to fold backinto a flap. A laser is then used to re-shape the cornea and correctvision acuity.

All three procedures can result in corneal epithelial defects, andinflammation and infection may also occur. These complications can leadto acuity regression, pain, or other adverse effects. Corneal defectsfrom injury or other types of surgery, such as corneal transplants, mayalso results in these undesirable outcomes. Wound healing is thus ofcritical importance for the outcome of surgery. There exists a need,therefore, for devices and treatments that promote healing of cornealwounds.

SUMMARY OF THE INVENTION

The present invention features hydrogel drug delivery systems andmethods of producing and using such systems for the treatment of wounds.The systems are based on a hydrogel into which a growth factor, e.g.,epidermal growth factor (EGF), is passively transferred from a diluteaqueous solution. When placed in contact with a wounded tissue, thegrowth factor passively transfers out of the hydrogel to provideaccelerated healing and a concomitant reduction in pain. The amount ofgrowth factor absorbed into the hydrogel may be ≦350 ppb, but thisamount surprisingly is effective in producing a therapeutic effectlikely because the delivery system is localized and provides a sustainedrelease of the factor. Higher concentrations of growth factor may alsobe employed. The systems are applicable to ocular wounds, especiallyafter vision correcting surgery, as well as other wound treatments.

Accordingly, in one aspect, the invention features a polymeric hydrogelthat contains a substantially pure growth factor. Exemplary growthfactors include epidermal growth factor, platelet derived growth factor,hepatocytic growth factor, human growth hormone, fibroblast growthfactor, and combinations thereof. The concentration of the growth factoris, for example, between 0.005 and 350 ppb. Other exemplaryconcentrations include at most 1, 10, 25, 50, or 100 ppm. The hydrogelhas a water content of, for example, between 37.5% and 75% by weight.Exemplary hydrogel materials include a tetrapolymer ofhydroxymethylmethacrylate, ethylene glycol, dimethylmethacrylate, andmethacrylic acid. Other examples of hydrogels include etafilcon A,vifilcon A, lidofilcon A, vasurfilcon A, and polymacon B. In addition,variations of these polymers formed by the use of different packingsolutions (e.g., phosphate-buffered saline and boric acid) in themanufacturing process are also included. The hydrogel may be ionic ornon-ionic. In various embodiments, the growth factor is capable of beingpassively released into an environment, e.g., an ocular environment,under ambient or existing conditions. In other embodiments, the hydrogelmay be shaped as a contact lens, e.g., one capable of correcting vision.Such a contact lens may be capable of correcting vision in the range of+8.0 to −8.0 diopters, including plano, and may have a base curvebetween 8.0 and 9.0. Hydrogels of the invention may further includeother therapeutic compounds as described herein, e.g., ananti-inflammatory compound, such as dexamethasone, fluorometholone,rimexolone, or prednisolone.

In another aspect, the invention features a polymeric hydrogel includingan anti-inflammatory compound. Exemplary polymers and anti-inflammatorycompounds are as described above. The concentration of theanti-inflammatory compounds is, for example, between 0.001 and 100 ppm,e.g., at most 0.01, 0.1, 1, 10, 15, 20, 30, or 50 ppm.

The invention further features a method for making a hydrogel drugdelivery system by placing the hydrogel, e.g., a contact lens, in anaqueous solution containing a substantially pure growth factor asdescribed herein, which is passively transferred to the hydrogel. Thismethod may further include the steps of washing the hydrogel in anisotonic saline solution and partially desiccating the hydrogel prior toplacement in the solution. The aqueous solution has, e.g., a pH between6.9 and 7.4 and between 0.01 and 10 ng growth factor per μL. Theconcentration of growth factor in the hydrogel after soaking (i.e.,after the medicated hydrogel is manufactured) is, for example, between 5and 350 ppb. In one embodiment, the hydrogel is placed in the solutionof growth factor for at least 30 minutes. The aqueous solution mayfurther include another therapeutic compound as described herein, e.g.,an anti-inflammatory compound, such as dexamethasone, fluorometholone,rimexolone, or prednisolone. Hydrogels containing these othertherapeutic compounds may also be obtained by omitting the growth factorin the soaking solution.

In another aspect, the invention features a method for treating a wound.The method includes placing a hydrogel, as described herein, in contactwith the wound, wherein the growth factor or anti-inflammatory compoundor both are passively released from the hydrogel to treat the wound. Inone embodiment, the hydrogel further acts as a protective shield againstmechanical abuse. In various embodiments, the wound is in endothelialtissue, epithelial tissue, the lung, the skin, or the digestive tract.The hydrogel may be placed in a body cavity. In another embodiment, themethod causes a reduction in pain compared to a wound not contacted withthe medicated hydrogel. The hydrogel may passively release, for example,at least 0.01, 0.05, 0.1, 0.5, 1, 10, 15, or 20 μg of a growth factor,and the hydrogel may be placed in contact with the wound for at least0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours. Thehydrogel may also passively release at least 0.01, 0.05, 0.1, 0.5, 1,10, 15, 20, 50, 100, or 1000 μg of other compounds, as described herein.

The invention also features a method of delivering a growth factorincluding the steps of placing a polymeric hydrogel of the invention incontact with a wound that is in contact with a replenishable bodilyfluid; and allowing the growth factor to release passively from thehydrogel into the replenishable bodily fluid. In this method, therelease of the growth factor from the hydrogel into the replenishablebodily fluid is accelerated compared to the release of the growth factorfrom the hydrogel into a non-replenishable bodily fluid. An exemplarywound is an ocular wound, and an exemplary replenishable bodily fluid istear fluid. This method may also be used to deliver anti-inflammatory orother compounds as described herein.

As used herein, by “ambient conditions” is meant room temperature andpressure.

By “existing conditions” is meant in situ, as in the eye or other bodysystem.

By “substantially pure” is meant having a purity of greater than 75% byweight. A growth factor of the invention is, for example, greater than85%, 90%, 95%, or even 99% pure. Use of the term is intended to definepurity from other biological compounds, e.g., proteins, carbohydrates,and lipids that are commonly associated with the growth factor in vivo.

By “treating” is meant the medical management of a patient with theintent that a prevention, cure, stabilization, or amelioration of thesymptoms will result. This term includes active treatment, that is,treatment directed specifically toward improvement of the disorder;palliative treatment, that is, treatment designed for the relief ofsymptoms rather than the curing of the disorder; preventive treatment,that is, treatment directed to prevention of the disorder; andsupportive treatment, that is, treatment employed to supplement anotherspecific therapy directed toward the improvement of the disorder. Theterm “treatment” also includes symptomatic treatment, that is, treatmentdirected toward constitutional symptoms of the disorder. The termfurther includes the promotion of wound closure or healing.

By “therapeutically effective amount” is meant an amount of a compoundsufficient to produce a preventative, healing, curative, stabilizing, orameliorative effect in the treatment of a condition, e.g., an eye wound.

By “wound” is meant an injury to any tissue. Examples of wounds includeburns, lacerations, abrasions, bites, surgical wounds, puncture wounds,and ulcers.

By “ocular environment” is meant the tissues of and surrounding the eye,including, for example, the sclera, cornea, and other tissues of theocular cavity.

By “replenishable bodily fluid” is meant a fluid produced by a mammalthat is periodically replaced with new fluid. Examples of replenishablebodily fluids include tears, saliva, mucous, gastric fluids, and urine.

All percentages described in the present invention are by weight unlessotherwise specified.

Other features and advantages of the invention will apparent from thefollowing description and the claims.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A and 1B are groups of the uptake (A) and release (B) of EGF fromvasurfilcon A contact lenses.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a polymeric drug delivery system including ahydrogel containing a growth factor, e.g., EGF. Allowing passivetransference of the growth factor from a dilute aqueous solution intothe hydrogel produces the delivery system. The hydrogel, when placed incontact with a wound, delivers a low concentration of the growth factor.The delivery of the growth factor is sustained over an extended periodof time, which is of particular utility in environments, e.g., the eye,that are periodically flushed with bodily fluids, e.g., tears. Thissustained delivery accelerates the wound healing process while avoidingpotential damaging effects of localized delivery of high concentrationsof compounds, e.g., from eye drops.

Drug Delivery System

Hydrogels. This invention may employ different polymer compositions thatare useful in the treatment of a variety of tissues. For example, in theocular environment, conventional soft contact lenses can be used and canbe either ionic or non-ionic hydrogels containing between 37.5%-75%water by weight and can have any base curve, e.g., from 8.0 to 9.0. Thecontact lenses may also have the ability to correct vision, for example,over a range of diopters of +8.0 to −8.0, including plano. Exemplaryhydrogel contact lens materials include etafilcon A, vifilcon A,lidofilcon A, polymacon B, vasurfilcon A, and a tetrapolymer ofhydroxymethylmethacrylate, ethylene glycol, dimethylmethacrylate, andmethacrylic acid. These materials may also be employed, in otherphysical forms, in treating wounds in other tissues. Other suitablehydrogel materials are known to those skilled in the art. The hydrogelsmay be insoluble or may dissolve over time in vivo, e.g., over one dayor one week. The growth factor is passively delivered, for example, bydiffusion out of the hydrogel, by desorption from the hydrogel, or byrelease as the hydrogel dissolves.

The drug delivery system may be produced from a partially desiccatedhydrogel (or equivalently a partially hydrated hydrogel). Thedesiccation step removes, for example, approximately 5%, 10%, 15%, 20%,25%, 30%, 40%, 50%, 60%, or 75% of the water in a hydrogel. Desiccationcan occur, for example, by exposure of the hydrogel to ambient orhumidity controlled air, by heating the hydrogel for a specific periodof time, or by blowing dried gas, such as N₂, over the hydrogel. In oneembodiment, the hydrogel is saturated with physiological (isotonic)saline prior to desiccation. The partially desiccated hydrogel is thensoaked, e.g., for at least 30 minutes, in a dilute aqueous solution ofgrowth factor, e.g., at a pH between 6.9 to 7.4. The hydrogels may alsobe soaked for at least 1 hour, 6 hours, 12 hours, or 24 hours. Theconcentration of growth factor into which the hydrogel is placed istypically 10 ng/μL or less, e.g., at most 5 ng/μL, 1 ng/μL, 0.1 ng/μL,or 0.01 ng/μL. Higher concentrations may also be used, for example, toreduce the soaking time. The growth factor is passively transferred intothe hydrogel. This transfer may occur at least in part by rehydratingthe hydrogel. Diffusion of the growth factor into the water in thehydrogel may also occur. In alternative embodiments, a fully hydrated orfully desiccated hydrogel is placed in the soaking solution to producethe medicated hydrogel.

Desirably, the concentration of growth factor transferred to thehydrogel is substantially lower than the solution in which the hydrogelis soaked. For example, the concentration of growth factor in thehydrogel is at least 2×, 5×, or 10× less than that of the soakingsolution. Some growth factors, however, may have a higher affinity for ahydrogel than aqueous solution, and such a hydrogel will have a higherconcentration of growth factor than the solution in which it was soaked.The water content and type of hydrogel, time and conditions, e.g.,temperature of soaking, composition of the soaking solution (e.g., ionicstrength and pH), and type of growth factor employed also may influencethe concentration of growth factor in the drug delivery system. Sincethe water content of the hydrogel also helps to determine the totalamount of growth factor present in a hydrogel, it represents a variableby which to control the amount of growth factor delivered to a tissue.The production of a hydrogel containing a specified amount of growthfactor can be accomplished by routine experimentation by one skilled inthe art. Exemplary hydrogels include between 5 and 350 ppb of growthfactor, for example, between 5 and 250 ppb, 5 and 100 ppb, 5 and 50 ppb,or 5 and 10 ppb. The concentration of growth factor in the hydrogel may,however, be higher, e.g., at most 100, 75, 50, 25, 10, or 1 ppm.

Growth Factors. Growth factors are a heterogeneous group of proteinscapable of stimulating growth and the multiplication of cells. Exemplarygrowth factors include epidermal growth factor, platelet derived growthfactor, hepatocytic growth factor, human growth hormone, fibroblastgrowth factor, and combinations thereof. These growth factors may benatural, synthetic, or recombinant growth factors or growth factorderivatives from any animal, for example, humans, or any domesticatedanimal or pet species. Such growth factors also include biologicallyactive growth factors and analogs. Peptide growth factors play importantbiological roles by regulating many of the processes involved in normalwound healing including migration, mitosis, and differentiation ofcells. Growth factors are commercially available or may be isolatedusing methods known in the art.

Other Compounds. The hydrogels of the invention may also containmedicaments other than growth factors. These additional compoundsinclude, without limitation, analgesics, anti-inflammatory drugs (e.g.,dexamethasone, fluorometholone, rimexolone and prednisolone),antibodies, meganins, self-proteins, pharmaceutical drugs, andantibiotic compounds. These other compounds may also be used at reducedconcentrations from their typically prescribed dosages. For example,these chemicals may be delivered in concentrations of less than 100, 50,25, 10, 1, 0.1, 0.01, or 0.001 ppm at various sites (e.g., the eye) andunder different conditions (e.g. ambient or existing).

The use of preservatives is non-ideal as they may transfer to a hydrogelat a disproportionately high concentration and cause cytotoxicity.

Treatment. To treat a wound, a drug delivery system of the invention maybe placed in contact with a damaged tissue. When the system is shaped asa contact lens, the lens may simply be placed in the eye normally inorder to deliver the growth factor. In order to effect acceleratedhealing of other wounds, the hydrogel may be part of a bandage or may beadhered (e.g., by adhesives or sutures) to the wounded tissue. If thehydrogel is placed internally in a patient, the hydrogel isadvantageously biodegradable.

Hydrogels may be considered to be disposable and may be replaced after aspecified period of time, e.g., at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,4.5, 5, 7.5, 10, 15, or 24 hours. Alternatively, a hydrogel that has adepleted amount of growth factor may be recycled by desiccating andsoaking the hydrogel again.

Treatment Approaches

The invention may be used in conjunction with healing many types ofwounds, including, without limitation, ocular, oral, lung, digestivetract, skin, large intestine, small intestine, colon, and other woundsto endothelial, mucosal, or epithelial tissues. As stated above, theinvention provides accelerated healing by delivering a growth factor toan injured tissue. In certain embodiments, at least 0.01, 0.05, 0.1,0.5, 1, 5, 10, 15, or 20 μg of the growth factor is released from thehydrogel. This delivery occurs by passive transfer and allowsmedications to be released into fluids of the body, e.g., ocular fluid.The growth factor stimulates proliferation of cells surrounding a woundto close the wound and replace damaged cells. Because the growth factoris localized by the hydrogel, which provides greater control overrelease of the growth factor or drug, a lesser amount of growth factormay in many cases be needed to effect wound healing than if, e.g.,topical solutions, such as eye drops are used. Accelerated healing mayalso reduce the pain and inflammation associated with a particular woundand may help prevent infection. In addition, the hydrogel may also actas a physical barrier to provide protection from mechanical abuse and toprevent adherence of the healing tissue to adjacent tissues. The use ofhydrogels of the invention may also allow patients to be treated usingfewer applications than with traditional methods. For example, a patienttreated using the hydrogels of the invention may be able to be treatedonly once in a period of at least 48 hours.

In desirable embodiments, a hydrogel of the invention is used to treat awound that is in contact with a replenishable bodily fluid, e.g., tears.In these embodiments, the growth factor is released from the hydrogel ata more rapid rate than the release of the growth factor into a fixedvolume of fluid because as the bodily fluid is replenished, the growthfactor released is flushed away from the site of application causing anincrease in the relative rate of diffusion of the growth factor out ofthe hydrogel. The replenishing action of fluids such as tears may alsoeffectively increase the rate of diffusion of the growth factor into thefluid and lead to earlier onset of therapeutic activity. For medicatedhydrogels of the invention placed in contact with a non-replenishablebodily fluid (i.e., one where replacement is very slow or nonexistent onthe time-scale of drug release), lower concentrations of a drug may beused since the drug is not flushed from the site as quickly as in areplenishable fluid.

Ocular Wounds. In one embodiment, the wound is an ocular wound, e.g., incorneal epithelial, endothelial, or retinal tissue. The invention is ofparticular utility after vision correcting surgery, such as LASIK, PRK,or LASEK. Soft and collagen contact lenses may be utilized to minimizepost-surgical epithelial trauma and provide a stable healingenvironment. PRK typically requires a therapeutic contact lens for 3-4days, and post-operative therapeutic drops are often prescribed. In thepresent invention, the hydrogel may be shaped as a contact lens thatacts as a reservoir for the growth factor and can serve to protect theleading edge of wound healing from normal mechanical abuse. The growthfactor gradually delivered in a low concentration from the hydrogelobviates the need for therapeutic drops. Therapeutic drops often includehigh concentrations of drugs because the majority of the drop isexcreted from the eye in a short period of time. These highconcentrations can cause additional damage to a wound, which is avoidedby the use of the present, localized time-release drug delivery system.

A further understanding of the invention may be obtained from thefollowing non-limiting examples.

EXAMPLE 1 Production of a Drug Delivery System

An exemplary drug delivery system was prepared as follows. Contactlenses were removed from their package and rinsed with saline to removecontact lens packing solution. The hydrogel lens materials were allowedto desiccate for 10-30 seconds. The hydrogel lens materials were placedinto physiological saline that contained epidermal growth factor (EGF)at concentrations of 10 ng/μl or 5.0 ng/μl for at least 30 minutes.Lower concentrations may also be used. Longer passive transference timesmay also be used. Untreated or control lenses were placed inphysiological saline without EGF.

EXAMPLE 2 Healing of Ocular Tissue

Ocular cells were placed into a sterile plastic dish. This dishcontained a 5-mm disk. The purpose of the disk was to prevent cells fromgrowing in the covered area. When the disk was removed, a 5-mm “wound”or “hole” was present.

Contact lenses were then added to these cell sheets with the wounds. Thelenses were left in contact with the cell sheets for a minimum of 30minutes. Minimal medium was used to maintain the cell cultures. Cellswere incubated at 35° C.±2° C. in 5% CO₂. Contact lenses with or withoutEGF were produced as in Example 1. The contact lenses used werepolymacon B, vifilcon A, and lidofilcon A hydrogel polymers.

The cell sheets were then viewed over time, and the diameter of the holewas measured.

The results are expressed in terms of closure of the in vitro wound overtime.

Epithelial Cells and Tissue. Epithelial (rabbit corneal epithelialcells) cells were seeded on a dish and contacted with control andEGF-containing contact lenses. At 48 hours there was a 25% difference inthe closure rate between the EGF-treated cells and the non-EGF treatedcells. At 72 hours, there was a 43% difference in the closure ratebetween the EGF-treated epithelial tissue and the controls. The hydrogelmaterial that was used was vifilcon A, an ionic polymer with a watercontent of 55%. The polymer had been incubated with 10 ng/μL EGF for onehour at 4° C. prior to use in the experiments.

Closure rates were calculated by direct measurement of the diameter ofthe wound. Measurements were taken daily.

In a related series of experiments, a vifilcon A lens was incubatedunder the same conditions as above with 5.0 ng/μL of EGF and thencontacted with an epithelial “wound” as above. At 48 hours, there was a21% closure rate difference between controls and EGF treated hydrogelmaterials. At 72 hours, there was also a 21% difference in the closurerate. These results indicated that over a 72-hour period, the relativehealing rates remained essentially the same for the treated andnon-treated epithelial tissue, with the epithelial tissue treated withEGF always having an accelerated rate of healing.

The rate of wound healing increased with increased exposure of thehydrogel material to the wound. Further, compared to a wound notcontacted with any lens, at 48 hours there was a 31% difference in thehealing rates. Healing for tissue exposed to a lens soaked in 10 ng/μLof EGF increased from 14% at 48 hours to 25% at 72 hours.

Endothelial Cells and Tissue. Wounds caused in endothelial tissue(bovine corneal endothelial cells) were also healed by release of EGFfrom a vifilcon A lens. The lens, soaked in 10 ng/μL of EGF as above,showed a 73% difference in healing rates at 48 hours compared to acontrol. At 72 hours, the EGF-treated tissue had completely healed. Inthe control group, less than half (43%) of the tissue had healed. Thesame lens material exposed to 5 ng/μL of EGF showed a 31% difference inclosure rate at 48 hours between the EGF treated group and the controls.At 72 hours, 53% of the tissue had healed in the EGF treated group,compared to 43% in the control.

Lidofilcon A hydrogel (non-ionic, water content=70%) materials wereevaluated for their ability to deliver EGF to endothelial tissue toclose wounds. The concentration of EGF used in the soaking solution was10 ng/μL. At 48 hours, the EGF treated tissue showed a 54% increase inthe healing rate (wound closure rate) as compared to controls. At 72hours, there was a difference of 44%.

A third material, polymacon B, that is non-ionic and has a water contentof 38%, was also evaluated for the ability to deliver EGF to wounds. Thelenses were prepared using a soaking solution of 10 ng/μL of EGF. At 48hours, the wound was 60% closed in the treated group and 27% closed inthe non-treated group. At 72 hours, the difference in closure betweenthe treated and untreated groups was 62%. In the EGF treated group at 72hours, the wound had closed by 80%, while in the untreated group, thewound had closed by 46.8%.

EXAMPLE 3 Uptake and Release of EGF

The amount of uptake and release of EGF from a contact lens depends onthe water content or composition of the lens or both. Data werecollected on the uptake and release of EGF from two types of lenses,lotrafilcon A (24% water) and vasurfilcon A (74% water). Both of theselenses are non-ionic. For uptake studies, thirty lenses of each typewere placed in 25 mL of a solution containing 40 ppm of EGF. For releasestudies, the lenses produced by the uptake study were placed in 25 mL ofsolution not containing EGF after desiccation for 10-30 seconds. Forboth types of study, the amount of EGF in the solution was then measuredat defined time intervals. For vasurfilcon A, about 75% of the EGF insolution was taken up by the lenses after 6 hours (FIG. 1A), at whichpoint the lenses appeared to be in equilibrium with the solution, andabout 37% of the EGF taken up was released after 7 hours (FIG. 1B), atwhich point the lenses appeared to be at or near equilibrium. Therelease data indicate that contact lenses can deliver a sustained dosageof EGF over a period of time. For lotrafilcon A, surprisingly, nomeasurable amount of EGF was taken up or released by the lenses. Basedon a purely diffusional theory of uptake, at least some growth factorwould have been expected to be taken up in the water in the lotrafilconA contact lens. Two possible explanations for the differential uptake ofEGF by the two polymers studied are 1) a water content higher than 24%is needed for uptake of EGF and 2) the lotrafilcon A polymer ischemically (thermodynamically) or structurally (kinetically) unfavorablefor the entry of EGF.

EXAMPLE 4 Animal Tests

Contact lenses containing EGF, EGF and dexamethasone (ananti-inflammatory steroid), and human growth hormone (HGH) were testedin a rabbit model for efficacy and toxicity. New Zealand white rabbitswere anesthetized, and then both eyes were abraded with a needle. Acontrol contact lens was placed in the left eye, and a medicated contactlens was placed in the right eye of each rabbit for up to 4 hours priorto euthanasia. Control contact lenses (etafilcon A, an ionic lens with58% water content) were washed with phosphate-buffered saline (PBS)prior to insertion. Medicated contact lenses (etafilcon A) were preparedby briefly drying the lens and then soaking it in 400 ppb, 4 ppm, or 10ppm EGF or 400 ppb HGH in PBS for 24 hours. In another experiment,lenses were soaked in 200 ppb EGF and 12.5 ppm dexamethasone for 25hours. No toxicity was observed in the rabbits at any concentration ofEGF tested. Rabbits were visually scored on a 0-4 scale (0 being thebest and 4 being the worst) for corneal edema (which is a measure ofwound healing), inflammation, and exudate production.

EGF (lenses soaked in 400 ppb EGF) released from hydrogel contact lenses(right eye) healed wounds at an accelerated rate when compared tocontrol eyes (left eye) for the first two hours after treatment. Datafrom four rabbits are shown in Table 1.

In another experiment, in addition to being abraded, the rabbits eyeswere treated with a solution of lipopolysaccharide from E. coli O111:B4(1 mg/mL) to induce inflammation. Lenses soaked in 200 ppb EGF and 12.5ppm (see above) dexamethasone controlled inflammation and causedincreased wound healing (right eye) compared to control eyes (left eye).EGF controlled healing of wounds even if there was an increase ininflammation.

Rabbit eyes (right eye) treated with HGH released from a contact lens(400 ppb soak) had increased wound healing and reduction in inflammationcompared to control eyes (left eye) in rabbits. In addition, no toxicitywas observed to the ocular tissue.

TABLE 1 Wound healing with contact lenses containing EGF Time CornealEdema Inflammation Exudate (hours) Left Right Left Right Left RightRabbit 1 1 1 1 0 0 0 0 1.5 2 1 1 0 0 0 2 2 1 2 0 1 0 2.5 2 2 1 1 2 1 3 22 1 1 2 2 3.5* 2 2 2 2 3 2 Rabbit 2 1 1 1 1 0 0 0 1.5 1 1 0 0 0 0 2 2 21 1 2 2 2.5 2 2 1 1 1 3 3 2 1 1 2 2 2 3.5* 2 2 1 2 1 2 Rabbit 3 1 1 1 00 0 0 1.5 1 0 0 0 1 0 2* 1 0 0 0 0 0 Rabbit 4 1 1 0 0 0 0 0 1.5 1 0 0 00 0 2 1 1 0 0 0 1 2.5 1 1 0 0 0 0 3 1 1 0 0 0 0 3.5 1 1 0 0 0 0 4* 1 1 00 0 0 *death of the rabbit

TABLE 2 Wound healing and treatment of inflammation with contact lensescontaining EGF and dexamethasone Time Corneal Edema Inflammation Exudate(hours) Left Right Left Right Left Right Rabbit 1 1 1 1 1 0 0 0 1.5 1 11 0 0 0 2 1 0 2 0 0 0 2.5 2 0 2 0 0 0 3 2 0 2 0 0 0 3.5* 2 0 1 1 1 1Rabbit 2 1 1 1 1 0 0 0 1.5 2 1 2 0 0 0 2 2 1 2 0 0 0 2.5 2 1 2 1 1 0 3 21 2 0 2 0 3.5 2 1 2 1 1 1 4.0* 2 1 2 2 2 2 Rabbit 3 1 1 1 1 0 0 0 1.5 11 1 0 0 0 2 1 1 2 0 1 0 2.5 1 1 1 0 0 0 3.0* 1 0 1 0 0 0 Rabbit 4 1 1 11 0 0 0 1.5 1 1 1 0 0 0 2 1 1 1 0 0 0 2.5 1 1 1 0 1 0 3 1 1 1 0 2 0 3.51 1 0 0 0 0 4* 1 1 1 0 0 0 *death of the rabbit

TABLE 3 Wound healing with contact lenses containing HGH Time CornealEdema Inflammation Exudate (hours) Left Right Left Right Left RightRabbit 1 1 1 1 0 0 0 0 1.5 2 0 0 0 0 0 2 2 0 1 0 0 0 2.5 2 0 1 0 0 0 3 20 1 1 0 0 3.5* 1 0 1 1 0 0 Rabbit 2 1 1 1 0 0 0 0 1.5 1 1 0 0 0 0 2 1 11 0 0 0 2.5 1 0 1 0 0 0 3 1 0 1 0 0 0 3.5* 1 0 0 0 0 1 Rabbit 3 1 1 1 00 0 0 1.5 1 0 0 0 0 0 2 1 0 1 0 0 0 2.5 1 0 1 0 0 0 3.0 1 1 1 0 1 0 3.5*1 1 1 1 0 0 Rabbit 4 1 1 1 0 0 0 0 1.5 1 1 0 0 0 0 2 1 0 1 0 0 1 2.5 1 11 0 0 1 3 1 1 1 0 0 1 3.5* 1 1 0 1 0 1 *death of the rabbit

EXAMPLE 5 Human Testing

A polymacon B lens having 38% water content was soaked in 400 ppb EGFfor 24 hours. This lens was placed in a human patient suffering from arecurring epithelial defect that was not responsive to traditionalmedical treatments. Clinical efficacy (i.e., wound healing) was observedafter treatment with the medicated lens of the invention. Desirablytreatment lasts for at least one hour. This type of injury is normallytreated by the repeated introduction of eye drops, sometimes as often asevery 4-5 minutes. A contact lens of the present invention, however, wasable to produce a positive result with only one administration.

Other Embodiments

Modifications and variations of the described methods of the inventionwill be apparent to those skilled in the art without departing from thescope and spirit of the invention. Although the invention has beendescribed in connection with specific desirable embodiments, it shouldbe understood that the invention as claimed should not be unduly limitedto such specific embodiments. Indeed, various modifications of thedescribed modes for carrying out the invention, which are obvious tothose skilled in the art, are intended to be within the scope of theinvention.

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually to be incorporated by reference.

Other embodiments are within the claims.

1. A method for making a hydrogel drug delivery system, said methodcomprising: (a) placing a hydrogel having a water content of between37.5% and 75% in an aqueous solution of an anti-inflammatory compound,and (b) allowing said anti-inflammatory compound to be passivelytransferred into said hydrogel in a therapeutically effective amount,wherein said anti-inflammatory compound is present at a concentration ofbetween 0.001 and 100 ppm.
 2. The method of 1, wherein saidanti-inflammatory compound is dexamethasone, fluorometholone,rimexolone, or prednisolone.